The proposed renewal of the Mount Sinai Center for the Neuroscience of Mental disorders (CCNMD) is designed to remain a highly focused effort to elucidate the role of white matter, oligodendrocytes and myelin in schizophrenia. This proposal is informed by increasing evidence of white matter, myelin and oligodendrocyte abnormalities in schizophrenia in a variety of areas of scientific exploration. A failure in connectivity has been demonstrated to have a role in schizophrenia. Myelination and those factors that affect myelination, such as the function of oligodendrocytes, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendrocytes and myelin in schizophrenia. Imaging, neuroanatomical, genetic and gene expression studies have all supported abnormalities in these cells and processes and contribute to our hypothesis that oligodendrocyte dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome (see overview and specific project for detailed references). A broad set of methodologies and expertise will be brought to bear on the questions the CCNMD will pursue, including neuroanatomy, neuroimaging, molecular biology, molecular genetics, animal models neuropsychology, phenomenology, statistics, and data management. The CCNMD is comprised of 5 Cores: Core A, Administrative;Core B, Clinical;Core C, Brain Bank;Core D, Data Management and Statistics;and, Core E, Mouse Phenotyping. The projects of the CCNMD include: Project 1: (Hof/Tang) Oligodendrocyte and neuron pathology in cingulate cortex;Project 2: (O'Donovan/Owen) Genetic dissection of abnormal oligodendrocyte and myelin function in schizophrenia;Project 3: (Buxbaum/Sakurai) Neuregulin signaling in oligodendrocytes;Project 4: (Buchsbaum) Structure and function of white matter in schizophrenia;and, Project 5: (Friedman/Davis) White matter imaging correlates of functional outcome in schizophrenia.